Incorporation of positron emitting fluorine-18 (half-life=110 min) into aromatic ring systems plays a very important role in the development of novel biomarkers for utilization in Positron Emission Tomography (PET). Two major pathways are commonly used for this process, namely, electrophilic and nucleophilic fluorine substitution reactions.
Electrophilic fluorination reactions can only provide products with low specific activities (ca 1-5 Ci/mmol) because of the unavoidable addition of non-radioactive elemental fluorine (often called carrier fluorine) during the current production techniques for F-18 labeled fluorine. The combination of labeled fluorine and carrier fluorine is referred to as [18F] F2. A typical example of electrophilic radiofluorination can be summarized by the following reaction:

Low specific activity biomarkers prepared by electrophilic aromatic radiofluorination reactions with [F-18]fluorine and reagents derived from it are generally useful for monitoring enzyme-mediated processes (e.g., aromatic amino acid decarboxylase dependent transformation). However, they are unsuitable for investigation of biochemical processes such as receptor systems or enzyme inhibition.
Nucleophilic radiofluorination of aromatic rings, on the other hand, provides products with high specific activity (ca 1,000-10,000 Ci/mmol). Unlike molecular [F-18]fluorine which is obtained in 0.3-0.7 Ci levels, high specific activity [F-18]fluoride ion, which is the fluorinating agent for nucleophilic substitution reactions, is more conveniently prepared in large quantities (1-10 Ci). Facile displacement of certain leaving groups (e.g. nitro and quaternary ammonium moiety) in aromatic systems activated by electron withdrawing substituents (e.g. CHO, COCH3, NO2, CN, COOCH3) by high specific activity [F-18]fluoride ion is well documented and can be depicted as follows:

Simple deactivated aromatic rings, such as the example cited above, provide [F-18]fluorinated products in good radiochemical yields (30-80%). However, as the complexity of the aromatic ring system increases (which is the case with almost all the useful biomarkers) the radiochemical yields obtained by this reaction drops drastically. Further, aromatic compounds lacking electron withdrawing/deactivating substituents (i.e. CHO, CN, NO2 etc) fail to undergo this reaction. Two different routes have been formulated for aromatic nucleophilic fluorination reactions for rings that carry deactivating substituents (e.g. CHO, NO2, CN etc) as well as groups that are electron donating in nature (e.g. CH3, OCH3). The first reaction involves an acid catalyzed thermal decomposition of phenyl triazenes bearing electron donating or electron withdrawing groups on the aromatic ring as shown below:

The second approach for the nucleophilic fluorination of aryl derivatives substituted with electron donating or electron withdrawing groups involves utilization of iodonium salts as depicted below:

While the radiochemical yield for this reaction is generally good with simple substrates, the radiolabeled fluorine (i.e. 18F) can end up on either of the phenyl rings. Thus, essentially this reaction provides a mixture of two F-18 labeled products; usually one of them is the desired product while the second one is an unwanted product. The percent distribution of the radiolabeled fluorinated products depends upon the electron donating/electron withdrawing nature of the substituent (i.e. R1 and R2) on the phenyl rings. In these iodonium salts, the phenyl ring carrying an electron withdrawing group is invariably radiofluorinated in higher yields than its counterpart phenyl ring substituted with an electron donating group. To obviate this shortcoming a new class of iodonium salt having a thiophene ring system has been advanced. Reaction of this thiophene
iodonium salt with no carrier added F-18 fluoride ion has been reported to yield [F-18]fluorobenzene as the single radiolabeled product (T. L. Ross, J. Ermert, C. Hocke and H. H. Coenen, “Nucleophilic 18F-Fluorination of Heteroaromatic Iodonium Salts with No-Carrier-Added [18F]Fluoride.” J. Am. Chem. Soc., 129, pp 8018-8025 (2007)). However, later careful analysis of this reaction mixture has revealed that both [F-18]fluorobenzene and 2-[F-18]fluorothiophene were produced (M. Carroll, C. Jones and S.-L. Tang, “Fluoridation of 2-thienyliodonium salts”. J. Label. Compd. Radiopharm., 50, pp 450-451 (2007)).
Thus, there is a great need for fluorination reactions and particularly for nucleophilic aromatic fluorination reaction conditions that are suitable for the preparation of F-18 labeled biomarkers having a variety of substituents, including electron donating groups. Using such reactions will make many different biomarkers easily accessible and will facilitate development and use of molecular imaging probes for PET. It is also anticipated that similar reactions with various nucleophiles would expand the utility of the approach to a multitude of labeled and unlabeled molecules.